title: T-cell co-stimulatory blockade in transplantation: two steps forward one step back!
abstract: BACKGROUND
  The concern about nephrotoxicity with calcineurin inhibitors led to the search of novel agents for immunosuppression. Based on the requirement of T-cell co-stimulatory signals to fully activated naïve T cells, it became clear that blocking these pathways could be an appealing therapeutic target. However, some unexpected findings were noticed in the recent clinical trials of belatacept, including a higher rate of rejection, which warranted further investigation with some interesting concepts emerging from the bench.
  
  
  METHODS
  This article aims to review the literature of the B7:CD28 co-stimulatory blockade in transplantation, including the basic immunology behind its development, clinical application and potential limitations.
  
  
  CONCLUSIONS
  Targeting co-stimulatory pathways were found to be much more complex than initially anticipated due to the interplay between not only various co-stimulatory pathways but also various co-inhibitory ones. In addition, co-stimulatory signals have different roles in diverse immune cell types. Therefore, targeting CD28 ligands with cytotoxic T lymphocyte antigen-4 (CTLA4)-Ig may have some deleterious effects, including the inhibition of regulatory T cells, blockade of co-inhibitory signals (CTLA4) and promotion of Th17 cells. Co-stimulatory independence of memory T cells was another unforeseen limitation. Learning how to better integrate co-stimulatory targeting with other immunosuppressive agents will be critical for the improvement of long-term graft survival.
authors.affiliation: Brigham & Women's Hospital, Boston Children's Hospital, Harvard Medical School, Transplantation Research Center, Renal Division , 221 Longwood Ave, Boston MA 02115 , USA +1 617 732 5259 ; +1 617 732 5254 ; lriella@rics.bwh.harvard.edu.
authors.forename: Leonardo V
authors.initials: LV
authors.lastname: Riella
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
mesh_terms: D000069594:Abatacept; D000818:Animals; D018122:B7-1 Antigen; D051940:B7-2 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D018106:CD28 Antigens / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000276:immunology; D002986:Clinical Trials as Topic; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000187:drug effects*; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use; D004198:Disease Susceptibility; D006082:Graft Enhancement, Immunologic / Q000379:methods; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D007156:Immunologic Memory / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007239:Infections / Q000209:etiology; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000187:drug effects; D008232:Lymphoproliferative Disorders / Q000139:chemically induced; D058990:Molecular Targeted Therapy; D015337:Multicenter Studies as Topic; D011183:Postoperative Complications / Q000139:chemically induced; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D014181:Transplantation Immunology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D061025:Costimulatory and Inhibitory T-Cell Receptors; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D016572:Cyclosporine